Historically, the adult mammalian heart has been considered a terminally differentiated organ with limited capacity to regenerate after injury. In contrast, recent evidence has shown that the neonatal heart can regenerate through increased cardiomyocyte proliferation. This ability to regenerate in response to injury ends by seven days after birth in mice, corresponding to the exit of cardiomyocytes from the cell cycle. Although there is some evidence for a very low level of postnatal cardiomyocyte proliferation which can be increased after injury, it is insufficient to replenish lost cardiomyocytes after injury and re-establish proper heart function. One important hurdle for cardiomyocytes to overcome in reentering the cell cycle is the rigidity of the sarcomere structure, which must be disassembled for cytokinesis to occur. Such disassembly may require signals for cardiomyocyte de-differentiation, which is accompanied by multiple cellular changes including reactivation of gene expression programs restricted to the embryonic state. Thus, approaches that reactivate or increase postnatal cardiomyocyte proliferation could have a positive affect on cardiac repair and regeneration but their persistence would need to be carefully tuned to avoid cardiomyocyte dysfunction associated with a highly proliferative, de-differentiated state.
MicroRNAs (miRs) can have potent affects on gene expression and can alter cell phenotype by coordinately targeting multiple components in important cellular pathways. Several miR cluster or families are expressed in early development and play important roles in maintaining tissue specific progenitor identity. One such cluster, miR302-367, is expressed during early embryogenesis in embryonic stem cells and in the developing lung endoderm where it promotes a de-differentiated phenotype characterized by high levels of cell proliferation.
Accordingly, a need exists to understand the mechanisms of miR302-367, and thereby develop improved miRNA-based compositions and methods.